I. Field of the Invention
The present invention relates generally to the fields of medicine, molecular biology, and biochemistry. More particularly, methods and compositions involving PBEF and PBEF inhibitors, including preventative, therapeutic, and diagnostic applications for inflammatory lung diseases and conditions.
II. Background
Mechanical ventilation is a life-saving intervention in critically ill patients with respiratory failure due to acute lung injury (ALI), a devastating syndrome characterized by profound lung inflammation, vascular permeability, and protein-rich alveolar edema (Rubenfeld et al., 2005; Ware and Matthay, 2000). Unfortunately, mechanical ventilation also potentially contributes directly to lung injury, a process known as ventilator-induced lung injury (VILI) with augmented capillary leakage, acute inflammation, and increases in inflammatory cytokine expression (Ranieri et al., 1999; Dreyfuss et al., 1988; Tremblay et al., 2002; Slutsky and Tremblay, 1998; Tremblay et al., 1997). The clinical relevance of VILI was highlighted by the landmark ARDSnet trial which reported decreased mortality in ARDS patients placed on low tidal volume ventilation, accompanied by decreases in BAL leukocytes and inflammatory cytokines (The acute respiratory distress syndrome network, 2000; Parsons et al., 2005).
Despite improved understanding of ALI pathophysiology, the underlying mechanisms of the injurious effects of mechanical ventilation in the setting of ALI remain unclear and effective pharmacotherapy has not yet emerged.